Prostate cancer is the most frequently diagnosed malignancy in American men, and is second only to lung cancer as a cause of cancer-related deaths. Considerable epidemiological data suggest that a diet rich in fats, beef and dairy products (major components of the Western diet) correlates with an increased risk of prostate cancer. Despite this long-known correlation, a mechanistic explanation for this association between diet and cancer has not yet been defined. Interestingly, it has recently been determined that 1-methylacyl- CoA racemase (AMACR) is overexpressed in greater than 90% of prostate cancers and hence, is now a standard biomarker for prostate cancer diagnosis. AMACR is an enzyme that converts unusable dietary branched-chain fatty acids to a metabolizable form. In our preliminary studies, we have generated data indicating that AMACR is androgen-regulated and promotes cell growth and survival by conferring cells the ability to utilize these branched-chain fatty acids. The primary goal of this proposal is to identify the connections between androgen signaling, important for both prostate physiology and pathology, and ingestion of branched-chain fatty acids, a major component of the Western diet, in prostate tumorigenesis. Here, a combination of in vitro and in vivo assays will be used to 1) Determine the mechanism(s) by which androgens and branched-chain fatty acids regulate prostate cell growth and survival and 2) Evaluate the impact of a branched-chain fatty acid-rich diet on prostate cancer in vivo. In this latter aim, we will use both transgenic and xenograft models of prostate cancer to facilitate our understanding of the influence of branched-chain fatty acids on cancer initiation and provide early mechanistic explanations for this link. Our findings will have direct implications for the improvement of dietary recommendations for at-risk patients. We expect that patients with elevated AMACR levels would be the most likely to benefit from a designer diet approach that functions to essentially starve potential cancer cells using a non-invasive and safe approach. Hence, collectively the results of this project will provide a rational for the implementation of a refined anticancer diet. Finally, this proposal will contribute to our overall understanding of how the environment functions in concert with potential oncogenic signaling processes to promote prostate cancer. PUBLIC HEALTH RELEVANCE: For years it has been known that a diet rich in ruminant fats, beef and dairy products (components of the Western diet) increases a man's risk of developing prostate cancer. Despite this known link, it is not fully understood why these foods put men at risk. This proposal investigates whether a specific aspect of the Western diet, namely branched-chain fatty acids, promotes prostate tumorigenesis. Understanding how certain diets impact cancer risk will maximize disease prevention by facilitating the improvement of dietary recommendations.